PROJECT SUMMARY The goal of this midcareer investigator award is to establish protected time through which I can direct greater focus towards mentoring young investigators interested in conducting patient oriented HIV-1 research. I am an internist trained in infectious disease with research that focuses on mucosal HIV-1 transmission and persistence. My career passion has always been to conduct patient oriented research that may ultimately improve diagnostics, treatment, or prevention of disease. Receipt of outstanding mentoring during various stages of my training allowed me to become a physician investigator and pursue my passion. My research primarily focuses on topics deemed high priority areas by the National Institutes of Health and relevant for patient health. Specifically, aims of this proposal will elucidate mechanisms for HIV-1 mucosal acquisition, the most common mode of transmission in the world. My group has identified novel epithelial-based cells that are potentially the first cell infected after mucosal exposure. R01AI122209 and this award will allow me to mentor trainees in examining how these unique epithelial cells impact the types of virus that establish infection in exposed hosts and how these cells can be source of the virus that re-emerges among virologically suppressed patients that stop taking antiretroviral therapy. I am also a practicing clinician, and in clinical practice, it has been noted that HIV infected patients are getting older and majority of patients suffer from HIV associated non AIDS (HANA) conditions, such as atherosclerosis, neurocognitive decline, and renal pathology. While studies have shown that systemic inflammation associates with HANA conditions, mechanisms for persistent inflammatory state in the absence of peripheral virus replication remain unknown. R01AG060890 along with this award will fund young-investigators to understand how HIV-1 expression from persistently infected cells induces systemic inflammation. This understanding will provide important information for developing novel therapeutic strategies aimed at ameliorating the burden of HANA diseases. We have also developed a novel antibody dependent cellular cytotoxicity (ADCC) assay because this antibody functionality has been deemed important in preventing transmission and decreasing the persistence of infected cells. R21AI137119 will fund optimization of the ADCC assay, and this optimized assay will be used to examine its role in preventing breast milk transmission by reducing the number of cells harboring infectious virus. K24 funds will allow me to pursue these patient oriented research aims, and it will augment my ability to train the next generation of researchers, especially clinician-scientists, so that they may gain skills in modern scientific methods to make an impact on human disease. At this time, there is a special need for future clinician-scientists because clinically trained physicians are often not pursuing research after their clinical training. I am particularly suited to accomplish this goal because I have trained numerous young investigators, including clinician-scientists, who have gone on to have independent research careers.